Collagen is the structural protein of connective tissue in fibrous form. A distinction is made between collagen of types I, II, III, X, etc., as a function of the structure, pharmacological action, and type of origin. Collagen fibers or fibrils are substantially obtained from comminuted Achilles tendons or from the subcutaneous tissue of cattle and horses. Due to the continuing problems with BSE, today collagen of bovine origin is practically no longer used. Collagen is obtained by gentle hydrolysis. It is a high molecular weight protein and a physiological substance.
The raw material obtained according to the known process goes through different cleaning and preparation steps and is finally usually lyophilized, and the final product accumulates in the form of highly porous, fibrous plates that are marketed in the size of a few square centimeters (e.g., 5×5, 5×10, 10×10 cm) with a thickness of ca. 3-6 mm and a weight of ca. 50-250 g/m2, preferably 70-130 g/m2.
Sterilization usually takes place by treatment with γ-rays. Commercial collagen sponges usually also contain an antibiotic for the prophylaxis of infection, with gentamicin but also vancomycin being used in particular. The gentamicin content is, for example, 1.3 mg base, corresponding to 2 mg sulfate per cm2. In order to improve the stability of the sponges, which collapse, swell, and dissolve in the wet state, crosslinking of the fibers is carried out, if necessary, by a chemical treatment with, e.g., glutaraldehyde or formaldehyde.
However, this treatment is not harmless from a toxicological viewpoint. Furthermore, it adversely affects the hemostyptic action and reduces resorption. Resorption takes place by the activity of migrating macrophages and by collagenases. Different half-lives are determined by the solubility behavior as a function of the degree of crosslinking. In an animal experiment a resorption time of greater than 40 days was observed after s.c. implantation of bovine collagen (sponges) in rats. In bone surgery in rabbits the resorption time was greater than 3-6 weeks (Monograph: Collagen, Animal Origin, Bundesanzeiger No. 149, Aug. 10, 1994). Basically, the collagen resorption is influenced by the site of application, by the amount and type of the collagen implant, as well as by the natural or aldehyde crosslinking that is present.
Substantial areas of clinical application for collagen sponges are, among others, wound overlays for local hemostasis, the coating of tissue defects, skin replacement in the case of lesions, skin covering in the case of large-area burns, the filling of bone defects, e.g., after cystectomies, even in the jaw region.
The hemostyptic (hemostasis) characteristics of the collagen (type I) obtained from animal skin are explained by the contact of the blood platelets with the native triple-helical structure of the collagen with simultaneous activation of blood coagulation. The fibril structure of the native collagen and its polar molecular structure are essential for platelet aggregation. Porcine material, namely, pigskin (e.g., DD 233 785 A1 and DD 292 840 A5) has already been described as the initial raw material for processes for the production of such collagen products determined as hemostyptics.
Known hemostyptics of native collagen usually have a very low pH, typically less than pH 6. As a consequence, wound healing problems can occur.
On the other hand, European patent EP 428541 B1 shows the production of a collagen implant with a higher pH. For this, an oxygen buffer is added. However, no native collagen starting material but rather an atelocollagen is used for the production of the collagen implant. In distinction to native collagen starting substances, atelocollagens are readily soluble and not sensitive at greater than pH 6.5 in further processing. In spite of the high pH, an atelocollagen solidifies relatively simply. In the processing of native collagen, on the other hand, the acid stabilizes the collagen structure, probably by denaturing the protein strands. In the case of a rather high pH this effect no longer occurs, so that the structure decomposes. In comparison to telopeptide-containing collagen, that is collagens in which the telopeptides were not chemically removed, atelocollagens have lesser hemostatic action. Furthermore, implants produced from atelocollagens are as a rule brittle in the dry state and have little resistance to bending. On the other hand, in the wet state the implants produced from atelocollagens are as a rule no longer dimensionally stable and have only a very low resistance to tearing so that once a collagen implant becomes wet it can no longer be withdrawn from the wound and moved.
In spite of their frequent use in surgery and orthopedic and despite various changes in the production process carried out over the course of years, the products on the market that are primarily used for hemostasis after surgical interventions have significant disadvantages concerning their handling as well as their biological behavior.
Thus, it turns out in practice that the collagen materials, for example, in the form of sponges, often have too little water resistance, too long a resorption time, adhere to the surgical instruments and gloves, and bring about incompatibility phenomena, in which in part strong seroma formation and wound healing problems predominate.
Therefore, the water resistance is significant because immediately upon the application of the collagen materials they very rapidly receive tissue fluid and especially blood, therefore collapse and lose their spongy structure and rigidity. This has the consequence that the material can then no longer be correctly placed on wound surfaces and therefore corrections of position that are frequently necessary at the application site on the wound are no longer possible.
Furthermore, collagen materials often characteristically adhere to surgical instruments (scissors, clamps, forceps, etc.) or gloves as soon as they are wet, which makes correct, accurate placement on the wound extremely difficult. This characteristic proves to be extremely problematic and obstructive in particular in the more and more frequently practiced processes of minimally invasive surgery, since in these operations only a very small spatial freedom of mobility is given.
The long resorption time of ca. 20-40 days is a great disadvantage. The intended preferred application purpose, hemostasis, is namely achieved after a few minutes to hours and the actual purpose of the application is therewith achieved. Even the antibiotic added for the prophylaxis of infection is eluted very rapidly out of the collagen material, so that an antibiotic protection is ensured only for a few days. Accordingly, the collagen material is, rather, a danger in the case of a delayed bacterial colonization, since the antibiotic-free collagen can then serve in the wound as a nutrient medium for infectious pathogens, especially when the wound must be drained on account of a heavy secretion. Therefore, for these reasons a much shorter dwell time (resorption time) of the collagen material would be extremely desirable.
However, the decisive medical disadvantage of the commercial collagen materials is based on the frequently observed, partially very pronounced incompatibility phenomena. After application these phenomena rapidly lead to inflammatory processes with cellular necroses and a strong secretion (seroma formation) that disturbs and greatly delays the susceptible natural healing process. This frequently prevents regular wound closure. These phenomena have the result more and more frequently that surgeons and orthopedists do not use the actually desired and indicated usage of collagen materials since the described side effects cannot be accepted from a medical viewpoint and also a disturbed and delayed wound healing course should not be expected of the patient.